Certain classes of noninfections inflammatory and hyperpigmentation diseases of the skin, thermal injuries of the skin, and premalignant skin tumors induced by ultraviolet or x-ray radiation or viruses, particularly those diseases which are multifactorial with a genetic predisposition, have yet to find a therapy which is fully satisfying. The standard therapies generally consist of the administration of antimicrobial agents which, depending on the disease, result in varying degrees of clearing of the disease condition. None of them however completely clear the disease.
Prominent among these diseases are the ichthyoses, rosacea, acne vulgaris, psoriasis, various types of dermatitis, melasma and actinic lentigos, actinic keratoses, Bowenoid papulosus, condylomatous dysplasia, cervical carcinoma, Bowen's disease and lentigo maligna.
The ichthyoses are a group of uncommon genetic diseases characterized by extreme scaling due to abnormal stratum corneum and epidermal function. Patients suffering from ichthyoses require lifelong daily therapy. Severe disfigurement occurs in the less common inflammatory types such as congenital ichthyosiform erythroderma, lamellar and X-linked ichthyosis, and epidermolytic hyperkeratosis. Microbial infection occurs in only two of the inflammatory types, and infrequently. Current treatments for the ichthyoses include retinoids and .alpha.-hydroxy acids. Each of these is effective in only a minority of patients, and even in those cases where they are effective, these treatments are often toxic, either topically, systemically, or both.
Rosacea is an inflammatory disease due to abnormal sensitivity of the vasculature. Rosacea often results in secondary sebaceous gland hyperplasia and inflammation producing characteristic skin lesions. Treatments for rosacea generally involve the administration of antiinflammatory antibiotics such as Metronidizole.
Acne vulgaris is a multifactorial disease most commonly occurring in teenagers and young adults, and is characterized by the appearance of inflammatory and noninflammatory lesions on the face and upper trunk. The basic defect which gives rise to acne vulgaris is hypercornification of the duct of a hyperactive sebaceous gland. Hypercornification blocks the normal mobility of skin and follicle microorganisms, and in so doing, stimulates the release of lipases by Propinobacterium acnes and Staphylococcus epidermidis bacteria and Pitrosporum ovale, a yeast. Thus released, the lipases cause damage to the gland structure and surrounding tissue, and this results in the formation of inflammatory papules, pustules, and cysts. The appearance of comedos, which are free of these microbes and inflammation, is a further characteristic of this disease. In some patients suffering from the disease, the only manifestation is noninflammatory lesions. Among those with inflammatory lesions, however, comedos appear in all cases. The most common treatments for acne vulgaris are oral and topical antibiotics and retinoids, topical forms of sulicylic acid, sulfur, and benzoyl peroxide, and oral antiandrogens.
Psoriasis in an inflammatory multifactorial disease characterized by epidermal hyperproliferation, disruption of the stratum corneum, and local immunologic anomalies, with microbial infection occurring in half the lesions. About half of psoriasis lesions have positive cultures for Staphylococcus aureus. .beta.-Hemolytic Streptococcus is known to cause guttate psoriasis. Psoriasis lesions are sharply demarcated, firm erythematous plaques usually with white scale. These plaques occur predominately on knees, elbows, scalp, genitalia, and buttocks. Current treatments consist of topical applications of corticosteroids, tar, anthralin, methotrexate, azathioprine, etretinate, psoralens plus ultraviolet A light, and tar plus ultraviolet B light. Antimicrobial agents along rarely produce a beneficial effect.
Dermatitis is a descriptive term referring to poorly demarcated lesions which are either pruritic, erythematous, scaley, blistered, weeping, fissured or crusted. These lesions arise from any of a wide variety of causes. The most common types of dermatitis are atopic, contact and diaper dermatitis. Lesions of atopic and contact dermatitis usually occur on the face, neck, and flexural surfaces. In most patients, there is also a heavy growth of Staphylococcus aureus and .beta.-hemolytic Streptococcus. Diaper dermatitis results from contact irritation to urine and feces followed by opportunistic infections by mixed bacterial and yeast organisms. Contact dermatitis results from irritation or allergy to chemicals or toxins applied to the skin intentionally or by accident. Current therapies for these various forms of dermatitis include topical and systemic corticosteroids, antipruritics, antibiotics and topical tar. Antibiotics when used along have no more than a mild therapeutic value, however.
Seborrheic dermatitis is characterized by poorly demarcated, scaley erythematous patches with yellowish greasy scales. "Dandruff" is a mild form of this condition, localized to the scalp. This disease may involve any one, several, or all of the following sites: scalp, eyebrows, glabella, paranasal and chin folds, ears and retroauricular sulci, presternal interscapular regions, pubic regions, and intergluteal folds. Pityrosporum ovale, a yeast, has been shown to play a significant role in 75% of patients afflicted with sebhorreic dermatitis. Present therapies for this disease include corticosteroids, tar, sulfur, and antibiotics, including antiyeast agents. One antiyeast agent, ketoconazole, has been reported to improve or clear seborrheic dermatitis lesions in about 75% of the patients in a group study. Other antimicrobial agents have only a mild therapeutic effect upon the lesions.
Melasma and actinic lentigos result from melanocytic hyperplasia. Melasma occurs only on the face while the lentigos may occur at any site, especially areas exposed to sun. The only effective approved treatment is hydroquinone. In some cases, however, this product results in dyspigmentation.
Actinic keratoses are superficial inflammatory premalignant tumors arising on sun-exposed and irradiated skin. The lesions are erythematous to brown with variable scaling. Current therapies include excisional and cryosurgery, 5-fluorouracil cream and chemical peels. These treatments are painful, however, and often produce cosmetically unacceptable dyspigmentation.
Bowenoid papulosus is a tumor of the genitalia induced by premalignant wart viruses and usually afflicting men. Condylomatous dysplasia and cervical carcinoma in situ are premalignant tumors of the female genitalia, also induced by wart viruses. Known treatments for all three of these tumors are cryosurgery, 5-fluorouracil, trichloroacetic acid, podophyllin and interferon. These treatments are painful, however, and not very effective, and often fail to produce long-term remission. Furthermore, when used against Bowenoid papulosus, these treatments have been shown in some cases to produce cosmetically unacceptable dyspigmentation.
Bowen's disease is a superficial intraepidermal tumor of keratinocytes most commonly caused by ultraviolet irradiation. Approximately 5% of Bowen's disease tumors metastasize as squamous cell carcinoma. These tumors frequently cover large areas of the skin. Current treatments consist of excisional and cryosurgery and 5-fluorouracil cream.
Lentigo maligna is a premalignant tumor of melanocytes usually occurring on sun-exposed, usually facial skin of elderly patients. In up to 30% of cases of this disease, the tumors progress to invasive melanoma cancer. These tumors frequently cover large surface areas. Treatment of lentigo maligna usually consists of excisional or cryosurgery, although the application of azelaic acid is also effective in some patients.
Certain prior issued patents may be of potential relevance to this invention. U.S. Pat. No. 4,292,326 (Nazarro-Porro, Sep. 29, 1981), U.S. Pat. No. 4,386,104 (Nazarro-Porro, May 31, 1983), and U.S. Pat. No. 4,713,394 (Thornfeldt, Dec. 15, 1987), disclose the use of certain dicarboxylic acids as therapeutic agents for a variety of skin diseases. U.S. Pat. No. 4,067,997 (Kabara, Jan. 10, 1978) discloses the activity against yeast, fungus, and bacteria of a synergistic combination of a 12-carbon monocarboxylic acid glycerol ester and a phenolic compound, used as a food preservative. U.S. Pat. No. 4,557,935 (af Ekenstam, et al., Dec. 10, 1985) discloses the germicidal activity of hydrogen peroxide in a formulation with the monoglyceride esters of lauric and myristic acids. U.S. Pat. No. 3,535,422 (Cox, et al., Oct. 20, 1970) discloses the synergistic activity of benzoyl peroxide, sulfur and organic emollients to treat acne, stating that the organic emollients, of which glycerol esters of monocarboxylic acids are included as examples, are stabilizers of the active ingredients rather than active ingredients themselves.